This invention relates generally to the diagnosis and treatment of neurodegenerative diseases, including Parkinson's Disease.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized clinically by bradykinesia, rigidity, and resting tremor. Selective degeneration of specific neuronal populations is a universal feature of PD that contributes to the clinical symptomology which is poorly understood. The hallmark neuropathologic feature of PD is loss of midbrain dopaminergic (DA) neurons. While the majority of PD cases are sporadic, for which a combination of environmental and genetic factors are likely responsible, familial cases that result from monogenic mutations have also been identified in genes including α-synuclein, parkin, ubiquitin C-terminal hydrolase-1, DJ-1, PINK1, and LRRK2. Regardless of specific etiology, DA neurons in the A9 region (substantia nigra pars compacta; SNc) are considerably more vulnerable than DA neurons in the immediately adjacent A10 region (ventral tegmental area; VTA). A similar pattern of differential vulnerability is observed in rodent and primate models of PD, including toxic models utilizing 6-hydroxydopamine (6-OHDA) 5 and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), indicating that such differential vulnerability between A9 and A10 DA neuronal populations may be conserved between species.
It has recently been demonstrated that rodent A9 and A10 DA neurons have distinct gene expression profiles despite their many similarities (Grimm et al., Proc. Natl. Acad. Sci. USA 101: 13891-13896, 2004; Chung et al., Hum. Mol. Genet. 14: 1709-1725, 2005; Greene et al., Neurobiol. Dis. 18: 19-31, 2005). Such inherent baseline gene expression differences may create biochemical identities that underlie the different thresholds of vulnerability to pathophysiological processes. Indeed, it was recently shown that altering expression of several differentially expressed genes in cell culture did affect the vulnerability to neurotoxins.
Currently, little is known about the mechanism underlying the neurodegenerative process and the basis for its differential effects on the A9 versus the A10 dopaminergic neurons. Accordingly, disease management is largely limited to strategies that achieve symptomatic relief (e.g., by replenishing dopamine levels) rather than strategies that seek to prevent or delay neurodegeneration. Thus, better treatment methods are needed for treating and preventing neurodegenerative disorders that address the underlying molecular etiology of the disease.